Blood pressure is under polygenic control in both animals and man. This means that genes at two or more genetic loci influence blood pressure. The long range objective is to identify the specific genes involved in regulating blood pressure in the rat, and to understand in biochemical and physiological terms exactly how these genes work. I have described a genetic locus (named Hyp-2) which influences in vitro vascular responses to cobalt (Co++) in spontaneously hypertensive rats (SHR). Alleles at this locus co-segregate with an increment in blood pressure. Effects of dominance and genetic background, however, prevented a complete understanding of the effect of the Hyp-2 locus on blood pressure. New protocols are proposed to circumvent these problems. Since the work of others suggests that the smooth muscle memebrane of SHR is abnormally permeable to calcium (Ca++), we will determine if the greater sensitivity of SHR smooth muscle to Ca++ co-segregates with alleles at the Hyp-2 locus. Preliminary studies suggest that Na+ Ca++ exchange is abnormally low in SHR. This phenomenon will be further characterized and also studied for co-segregation with alleles at the Hyp-2 locus. Surveys of plasma-membrane proteins and phospholipids of vascular smooth muscle will be made to try to find a genetic polymorphism at the biochemical level which can be related to physiological responses controlled by the Hyp-2 locus. Chemically skinned smooth muscle will be utilized to separate contributions of the plasma membrane and the contractile proteins. Also the role of extracellular Ca++ in the Co++ induced response will be evaluated. Non-killikrein urinary TAME esterases are to be studied in inbred Dahl salt-susceptible (S/JR strain) and salt-resistant (R/JR strain) rats. We have isolated a new kinin generating enzyme (TAME esterase A2) from the urine of R/JR female rats. Preliminary data show that esterase A2 is largely absent in the urine of S/JR rats, but it is replaced by a different TAME esterase which is designated S/JR rat urinary TAME esterase A3. We will determine if the S/JR and R/JR strain differences in esterases A2 and A3 are due to a simple genetic polymorphism which can then be tested genetically for a relationship of blood pressure. Esterase A2 will be localized in the kidney by immunohisterochemical methods. Esterase A3 will be isolated and characterized with regard to kinin generation.